Pancreatic, lung cancer, ovarian cancer, brain cancer, and ovarian cancer remain some of the most difficult cancers to treat. As an example, pancreatic cancer is the fourth leading cause of cancer related deaths (ACS). In 2008 an estimated 37,680 people will be diagnosed with pancreatic cancer and 34,290 will die from the disease (ACS). The high rate of mortality for pancreatic cancer is mainly attributed to the tendency for late diagnoses as symptoms may not occur until the disease has metastasized as well as the lack of effective systemic therapies. This leaves surgery as an option in only 10-20% of pancreatic cancer patients and chemotherapy and radiation as the main therapeutic measures. Of those who are surgical candidates, less than 40% of the surgeries are curative, with most experiencing either recurrent pancreatic tumors or tumors that have metastasized to the liver. Both radiation and chemotherapy treatment options result in severe side effects that affect the patient's quality of life and many times fail to provide significant improvement in the disease. The standard chemotherapy treatment for advanced pancreatic cancer, gemcitabine, most commonly causes side effects of nausea, pain, fatigue, increased susceptibility to infection, renal toxicity and liver toxicity. The effectiveness of gemcitabine can also be limited by drug efflux mechanisms in tumor cells resulting in incomplete tumor responses. Although many clinical trials have been undertaken, gemicitabine has remained the standard of treatment for pancreatic cancer for the past decade. There is a clear need for improved therapies that have better efficacy and reduced side effects in the treatment of pancreatic cancer and other difficult to treat cancers.
The reaction achieved with Photodynamic Therapy (PDT) combines three individually non-toxic components, the photosensitizer, light and tissue oxygen to selectively destroy tissue. For tumor types other than skin cancer, PDT treatment involves an intravenous injection of photosensitizer, which is allowed to circulate within the body for a period of time to accumulate within the tumor site. This is followed by irradiation of the tumor site with light, most conveniently a laser, at the wavelength corresponding to the excitation maxima of the photosensitizer that was used. The light excites the photosensitizer to interact with tissue oxygen creating singlet oxygen species. The singlet oxygen species can then damage tumor cells directly, or via conversion to other reactive oxygen species, not limited to superoxide, hydroxyl radicals, peroxynitrates, hydrogen peroxide, and lipid peroxides. In this way, the localization of photosensitizer to tumor tissue, tissue oxygenation and dose of light are all critical factors in the outcome of PDT. Although PDT is currently approved for the treatment of esophageal cancer, lung cancer and skin cancers in the U.S. it is still limited in use due to short lifetimes of photosensitizers, an inability to penetrate sufficient light through tissue, and an inability to preferentially target cancerous tissues with photosensitizers (Allison, R. R., Bagnato, V. S., Cuenca, R., Downie, G. H., and Sibata, C. H. (2006) The future of photodynamic therapy in oncology. Future Oncol. 2: 53-71.).
Although several clinical trials are underway, Photofrin is the only FDA-approved photosensitizer for PDT cancer treatment. While Photofrin provides several advantages for the treatment of esophageal cancer, lung cancer and Barrett's esophagus, it still suffers from a short half-life and a lack of effective tumor localization. This results in suboptimal efficacy as well as systemic photosensitivity side effects. The development of the “second generation” photosensitizers which are now in clinical trials has focused on compounds with decreased photosensitivity reactions. However, these “second generation” photosensitizers as well as Photofrin, have maximum excitations at wavelengths less than 700 nm. This limits the tissue depth that current photosensitizers can be effectively used at since lower wavelengths have limited tissue penetration due to absorption by endogenous chromophores. For these and other reasons, there is a need for the present invention.